It has been known for many years that there are species, strain, and sex differences in the incidence and severity of the nephrotoxicity caused by chloroform. For example, DBA/2J - males are more sensitive than are C57/BL6 male mice and males of a given strain are more sensitive than are females. The molecular basis for these differences, however, has not been clearly understood. In this investigation, we have found that sensitivity to chloroform correlates with the capacity of the kidney to metabolize chloroform to the toxic metabolite phosgene. For instance, kidney homogenates from DBA/2J mice convert chloroform to phosgene approximately twice as rapidly as do those from C57/BL6 male mice, whereas kidney homogenates from ICR males metabolized chloroform to phosgene at nearly an order of magnitude more rapidly than do those from ICR female mice. Cytochrome P-450 in the microsomal and mitochondrial fraction of the kidney appears to catalyze this reaction and testosterone somehow regulates the activity of these enzymes.